1. Field of the Invention
The present invention relates generally to the fields of biochemical pharmacology and medicinal chemistry. More specifically, the present invention relates to high dose liposomal aerosol formulations of various pharmaceuticals, including cyclosporin A and budesonide.
2. Description of the Related Art
In the lung, many different diseases have been treated successfully through utilization of aerosol delivery systems used to deposit drugs directly on to the pulmonary surfaces. For delivery in this manner, a variety of devices have been developed (for example, metered dose inhalers and dry powdered inhalers). Jet-nebulizers have been used clinically for aerosol delivery of water soluble drugs and micronized suspensions; however, their use with water insoluble, hydrophobic compounds has been limited.
The development of liposomal formulations compatible with aerosol delivery has allowed the jet nebulizer to deliver additional drugs. Utilization of liposomes for aerosol delivery has many advantages, including aqueous compatibility; sustained pulmonary release allowing maintanence therapeutic drug levels, and, further, liposomes facilitate intra-cellular delivery, particularly to alveolar macrophages.
The efficacy of localized, topical therapy via aerosols is determined by the amount of drug delivered at the sites of disease within the lung; and there are several different key parameters that determine the amount of delivery, thus, the therapeutic efficacy of aerosol formulations. For example, nebulizer design and variation, operating conditions (e.g., flow rate), and the presence of ancillary equipment (tubing, connectors, mouth pieces, face masks, and the like), are important variables. Thus, aerosol output efficiency can be increased through proper implementation of the proper nebulizer device. Inappropriate implementation of the device and/or imperfect parameters can affect inhaled dosages, delivery sites and influence the therapeutic outcome.
Drug formulation also is a critical factor regulating aerosol output efficiency and aerodynamic properties of drug-liposomes. It has been discovered that drug-liposome output efficiency can be increased through the utilization of liposomes formulated with low phase transition temperatures (see Waldrep et al., J. of Aerosol Med. 7:1994 (1994) and Waldrep et al., Int'l J. of Pharmaceutics 97:205-12 (1993)). An additional method to increase aerosol drug-liposome output is to increase the drug and phospholipid reservoir concentrations. Nebulization of some drug-liposome formulations at greater than 50 mg/ml results in clogging of the nebulizer jets; yet empty liposomal formulations up to 150 mg/ml have been successfully nebulized (see Thomas, et al., Chest 99:1268-70 (1991)). Further, the aerosol performance (output and particle size) is influenced in part by physiochemical properties such as viscosity and surface tension. Such variables affect the maximal drug-liposome concentrations compatible with aerosol delivery via the jet nebulizer.
Anti-inflammatory glucocorticoids have been used for the treatment of asthma and other severe inflammatory lung diseases for over forty years. More recently, aerosol glucocorticoid therapy has been used increasingly as a route of administration. Presently, there are several different, though structurally similar, topically active glucocorticoids--e.g., beclomethasone, budesonide, flunisolide, triamcinolone acetonide and dexamethasone--that are available in metered dose inhalers or dry powder inhalers for aerosol treatment of asthma and other inflammatory diseases of the lung. While systemic complications such as suppression of the hypothalamic-pituitary axis, cataract formation and growth inhibition are infrequent in asthmatics treated with inhaled glucocorticoids, localized side effects of candidiasis and dysphonia are more common, necessitating the use of accessory spacer devices. At present in the United States, there are no glucocorticoid formulations approved for nebulized administration, although micronized suspensions of beclomethasone and budesonide are employed in Europe and Canada.
The present invention is drawn to concentrated, high dose cyclosporin-A-liposome and budesonide-liposome aerosol formulations that provide maximal aerosol output with particle size ranges within the optimal range of 1-3 .mu.m mass median aerodynamic diameter (MMAD). The prior art is deficient in such liposomal aerosol formulations. The present invention fulfills this long-standing need and desire in the art.